Citation:

Gray Jr., L E., J S. Ostby, J. R. Furr, M. G. Price, D. Veeramachaneni, AND L G. Parks. PERINATAL EXPOSURE TO THE PHTHALATES DEHP, BBP AND DINP, BUT NOT DEP, DMP OR DOTP ALTERS SEXUAL DIFFERENTIATION OF THE MALE RAT. TOXICOLOGICAL SCIENCES 58(2):350-365, (2000).

Description:

In mammals, exposure to antiandrogenic chemicals during sexual differentiation can produce malformations of the reproductive tract. Perinatal administration of AR antagonists like vinclozolin and procymidone or chemicals like di (2-bis) ethylhexyl phthalate (DEHP), that inhibit fetal testicular testosterone production, demasculinize the males such that they display reduced anogenital distance (AGD), retained nipples, cleft phallus with hypospadias, undescended testes, a vaginal pouch, epididymal agenesis, and small to absent sex accessory glands as adults. In addition to DEHP, di-n-butyl (DBP) also has been shown to display antiandrogenic activity and induce malformations in male rats. In the current investigation, we examined several phthalate esters to determine if they altered sexual differentiation in an antiandrogenic manner. We hypothesized that the phthalate esters that altered testis function in the pubertal male rat would also alter testis function in the fetal male and produce malformations of androgen-dependent tissues. In this regard, we expected that benzyl butyl (BBP) and diethylhexyl (DEHP) phthalate would alter sexual differentiation, while dioctyl tere- (DOTP), diethyl (DEP) and dimethyl (DMP) phthalate would not. We expected that the phthalate mixture, diisononyl phthalate (DINP), would be weakly active due to the presence of some phthalates with a 4-7 carbon side chain. DEHP, BBP, DINP, DEP, DMP, or DOTP were administered orally to the dam at 0.75 g/kg from gestational day 14 to postnatal day three. Although none of these treatments induced maternal or pup mortality, DEHP reduced maternal pregnancy weight gain by about 25 g. DEHP and BBP treatments reduced pup weight at birth. Male (but not female) pups from the DEHP and BBP groups displayed shortened AGDs (25%) and reduced testis weights (30%). As infants, males in the DEHP, BBP and DINP groups displayed female-like areolas/nipples (86%, 70% and 22% (p<0.01) respectively versus 0% in other groups). All three of the phthalate treatments that induced areolas also induced a significant incidence of reproductive malformations. The percentages of males with malformations were about 87Earl% (p < 0.0001) for DEHP, 84% (p < 0.0001) for BBP and 7.7% (p <0.04) in the DINP group. These phthalate esters produced a wide range of malformations of the external genitalia, sex accessory glands, epididymides and testes. In summary, DEHP, BBP, and DINP all altered sexual differentiation while DOTP, DEP and DMP were ineffective at this dose. While DEHP and BBP were of equivalent potency, DINP was about an order of magnitude less active.

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